Derivatives of cephalosporanic acid



United States Patent 3,117,126 DERIVATIVES OF CEPHALOSPORANIC ACID John R. E. Hoover, Glenside, and Bernard Loev, Broomall, Pa, assignors to Smith Kline 8; French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Oct. 1, 1962, Ser. No. 227,593 Claims. (Cl. 260-243) This invention pertains to novel compounds possessing valuable chemotherapeutic activity and more specifically to a new class of compounds demonstrating important antimicrobial properties.

This application is a continuation-in-part of our copending application Serial No. 49,443, filed August 15, 1960, now abandoned.

Our novel compounds are useful in the treatment of microbial infections many of which have heretofore been resistant to many of the known antibiotics. The administration of these compounds of the infected host may be accomplished in any of the usual forms, such as for example, solutions, suspensions, creams, ointmeuts, tablets, capsules, and the like, and are suitable for oral, injectable, or topical application, depending upon the nature of the particular infection.

The compounds of the present invention may be represented by the following structural formula:

in which A is lower alkanoyloxy, benzoyloxy, hydroxyl, pyridinium, or when taken together with M, a monovalent carbon-oxygen bond; M is hydrogen, a pharmaceutically acceptable cation, an anionic charge when A is pyridinium, or when taken together with A, a monovalent carbon-oxygen bond; Z is a vicinally bound structure selected from the group consisting of lower alkylene of from 2 to 6 carbon atoms, lower alkenylene of from 2 to 6 carbon atoms, lower cycloalkylene of from 4 to 6 carbon atoms, lower cycloalkenylene of from 4 to 6 carbon atoms, phenyl lower cycloalkylene of from 8 to 12 carbon atoms, phenyl lower cycloalkenylene, phenylene, lower alkylphenylene, halogenophenylene, lower alkoxyphenylene, pyridinylene, piperidinylene, pyrrolylene, pyrrolidinylene and piperazinylene.

In those instances where A is pyridinium, the cationic charge on this group is matched by the anionic charge of the carboxylic acid radical, the entire molecule being of a Zwitterionic nature and M thus being an anionic charge. A may also be hydroxy, a l to 6 carbon atom lower alkanoate or the benzoate thereof. The hydroxy group embraced by A may be internally esterified by the carboxylic acid radical of the isovaleric acid carbonoxygen skeleton thereby forming a lactone ring as represented when A and M taken together comprise a monovalent carbon-oxygen bond.

Also embraced within the scope of the present invention are the nontoxic pharmaceutically acceptable salts of the above carboxylic acid radical. The cations comprised in these salts and embraced by M include for example, the alkali metal ions as for instance the sodium ion, potassium ion, calcium ion as well as the organic amine cations, such as the lower alkyl ammonium groups, (as for instance triethylammonium), procaine, dibenzylamine, l-ephenamine, dehydroabietylamine and the like.

The symbol Z is employed to represent certain carbon 3,il7,l2 Patented Jan. 7, 1954 ice containing structures described herein which are bound to the two carboxy groups of the imido structure by two monovalent carbon-carbon bonds, one of each of said bonds arising from each of the two vicinal carbon atoms of the group represented by Z. Thus the imido structures of our invention embrace a five membered heterocyclic ring having a carbon skeleton similar to that found in a succinimide or maleimide:

I ll

The valence requirements of the four remaining bonds on the vicinal carbon atoms may be satisfied by the presence of four hydrogen atoms, i.e., succinimido; a double bond and two hydrogen atoms, i.e., maleimido; hydrogen and/or lower alkyl, i.e., ethylsuccinimido, a,,B-dimethylsuccinimido; hydrogen and alkylene or alkenylene groups, i.e., 4-cyclohexene-l,Z-dicarboxyimido, 3,3-dimetl1ylcyclobutane-l,Z-dicarboxyimido; phenylene, i.e., phthallimido; phenyl and hydrogen, i.e., a,B-diphenylsuccinimido; or heterocyclic ring structures, e.g., pyridine-2,3- dicarboxyimido, piperidinylene; 3,4-dicarboxyimido and pyrrole-2,S-dicarboxyimido; and the substituted analogs of the above.

The compounds of our invention are thus imido derivatives of certain heterocyclic nuclei and are prepared by treating a nucleus of the formula:

with an appropriate carbo-(loweralkoxy)-imido compound such as a carboethoxyimido or carbomethoxyimido derivative. This reaction may be represented as follows, employing the carboethoxyimido derivative as representative:

While it is possible to form the desired imido compound according to certain other known methods heretofore employed for preparing imido compounds, as for example treatment with a diacyl halide, we have found that better yields can generally be obtained in the imide formation and under less drastic conditions by employing the corresponding carbo-(loweralkoxy)-imido derivatives.

The required carbo-(loweralkoxy)-imido starting mateactant by treatment with ethylchloroformate.

Upon'hydrolysis of Cephalosporin C, as for example acid hydrolysis, there is formed a-aminoadipic acid and 7-aminocephalosporanic acid, the latter compounds structure being represented by the formula:

In addition to the formation of 7-aminocephalosporanic acid upon the acid hydrolysis of Cephalosporin C, there is also further formed by hydrolysis of the acetyloxy grouping the subsequent internal'esterification, the lactone having the formula:

These two products, designated by Formula V and Formula VI, are readily separated by virtue of the different physical properties, as for example by chromatographic techniques.

It is further possible to modify the structure of the acetyloxy side chain found in Cephalosporin C and 7-aminocephalosporanic acid. Thus the enzymatic cleavage of this ester without subsequent lactone formations, there is formed a compound containing a hydroxymethyl group in the 3-position of the thiazine ring of the Cephalosporin nucleus. Such a compound has been assigned the name of a 3-hydroxydecephalosporanic acid shown below devoid of substitution in the 7-position.

The designation decephalosporanic acid is herein employed to indicate the basic nucleus of cephalosporanic acid devoid of acetoxymethylene side chain and is inthe unknown basic heterocylclic acid nucleus having the formula:

The cleavage of the acetyloxy grouping to form 3-hydroxymethyl-7-aminodecephalosporanic acid without subsequent lactone formations may be accomplished by employing enzymatic means, as for example, by the action of an acetylesterase. Such suitable enzyme preparations may be obtained for example, from citrus fruits such as oranges, grapefruits, lemons and the like, as-described by Jansen et al., Arch. Biochem, 15, 415 (1947). Preparations of such an enzyme advantageously eifect hydrolysis of the acetyloxy side chain without subsequent lactone formation. The resultant hydroxy group may then be further modified as by re-esterification with a lower alkanoic acid or aralkanoic acid radical so as to form other lower alkanoate esters and the aralkan ic esters thereof.

As the conditions and reagents employed in acylating hydroxyl groups are similar to those for acylating amino groups, it is generally desirable in practice to aifect acylation of the hydroxyrnethyl group in the 3-position of decephalosporanic acid, after formation of the imido group in the 7-position. Deacetylation on either Cephalosporin C or 7-aminocephalosporanic acid according to the enzymatic techniques discussed herein followed by reacylation of the resultant hydroxyl group generally results in concurrent acylation of the amino group of the a-amino side chain adipic acid of Cephalosporin C or of the amino group in the 7-position of 7-aminocephalosporanic acid respectively. Thus in practice, Cephalosporin C is cleaved by acid hydrolysis as herein described to yield 7-aminoeephalosporanic acid which in turn is subjected to the procedures of this invention to obtain the 7-imido derivative of cephalosporanic acid. This compound may then be treated with acetylesterase as herein described to yield the corresponding compound containing a hydroxylmethyl group in the 3-position which in turn is reacylated by methods analogous to those known to the art, such as for example, by means of an acyl halide or acid anhydride.

An additional modification of these heterocyclic nuclei involves treatment of Cephalosporin C with a tertiary base such as for example, pyridine, 2,5-dimethylpyridine, quinoline, or eollidine prior to acid hydrolydic cleavage of the aminoadipic acid side chain whereby there is formed a quaternary salt derivative of Cephalosporin C. When hydrolyzed as herein described there is yielded a nucleus which, in the case of pyridine, has been assigned the name, 3-pyridiniummethyl-7-aminodecephalosporanic 'acid inner salt and the structure:

The preferred embodiment of our invention are these compounds of Formula I wherein R represents:

where A represents a lower allcanoyloxy, M is hydrogen or pharmaceutically acceptable cations, and Z is alkylene,

phenylalkylene, phenylene or substituted phenylene.

The following examples will further serve to typify the nature of this invention. These examples, however, are representative only of embodiments of our invention and should not be construed as limiting the scope of this invention, the scope being defined only by the appended claims.

Example 1 Four grams of Cephalosporin C as the sodium salt are dissolved in 60 ml. of water and the pH adjusted to 2.5 by the addition of the acid form of Dowex 50 (x8). The resin is filtered and washed with 20 ml. of water and to the combined filtrate and washings are added 20.5 ml. of 0.1 N hydrochloric acid. The mixture is allowed to stand for 72 hours at 20 C. and at the end of this time, introduced into a column of Dowex-l (as the acetate form), 2 cm. x cm. The initial percolate is collected in 10 ml. fractions and upon the collection of the twelfth fraction the column is eluted with water until a total of 34 fractions have been collected. The column is thereupon eluted with 0.5 N acetic acid and an additional 65 fractions collected.

Fractions 36 through 45 are combined and concentrated by freeze drying to yield 7-aminocephalosporanic acid.

Fractions 2 through 16 are combined and concentrated in vacuo to yield the lactone of desacetyl Cephalosporin C which when resubjected to the above acid hydrolysis procedure yields 3-hydroxymethyl 7 aminodecephalosporanic acid lactone.

By increasing the concentration of the acid in the above procedure from 0.1 N to 1.0 N and the length of reaction to four days the amounts of desacetyl Cephalosporin C lactone and 3-hydroxylmethyl-7-aminocephalosporanio acid lactone are increased.

Example 2 (A) One gram of Cephalosporin C as the sodium salt is dissolved in 50 ml. of water. There is then added sufficient Dowex 50 (x8) resin as the hydrogen form to adjust the pH to 2.6. The resin is removed by filtration and to the filtrate is added 3.8 ml. of pyridine, the pH rising to approximately 6.5. The solution is maintained in a glass container at 37 C. for 48 hours. At the end of this time the solution is freezed dried and the residue, triturated twice with 50 ml. of acetone and redried. The solid is then dissolved in 10 m1. of water and introduced onto a Dowex 1 (x10) acetate column (2 cm. x 10 cm.). The column is eluted with water and 10 ml. fractions are collected. Fractions 2 through 4 are then combined and freezed dried, and the residue stirred with acetone and dried to yield the pyridinium inner salt of desacetyl Cephalosporin C.

(B) This material is then subjected to the acidic hydrolydic procedure as described in Example 1. Upon chromatographic separation as described therein, the earlier fractions collected are combined and reduced to a residue to yield 3-pyridiniummethyl-7-aminodecephalosporanic acid inner salt. The latter fractions are combined and concentrated to a residue to yield the pyridinium inner salt of desacetyl Cephalosporin C which may be resubjected to the hydrolytic procedure to yield additional material.

Example 3 (A) To 204 g. (2 moles) of acetic anhydride are added 200 g. (1 mole) of 4-chlorophthallic acid. The mixture is heated until the solid dissolves and then heated for an additional minutes. At the end of this time, the reaction mixture is allowed to cool and the solid is then washed with a small amount of anhydrous ether which is free of ethanol and the washed solid then dried to yield 4-chlorophthallic anhydride.

(B) There is added to 130 ml. (1.9 mole) of 28% aqueous ammonium solution, a total of 182 g. (1.0 mole) of 4-chlorophthallic anhydride. A large bore condenser is attached and the mixture is heated over an open flame for 1Vz-2 hours, or until all the water has evaporated, generally requiring a temperature in the range of about 300 C. The mixture comprising essentially of 4-cl1loro phthallimide is then covered and allowed to cool and employed in the next step Without further purification.

(C) To a stirred solution of g. (0.5 mole) of 4-chlorophthallimide and 69 ml. (0.5 mole) of distilled triethylamine in 1 ml. of distilled dimethylformamide are slowly added at -5 C., 47.6 ml. (0.5 mole) of distilled ethylchloroformate. The addition rate is adjusted so that the temperature is maintained between -3 C. and 5 C. Upon completion of the addition, the reaction mixture is stirred at 0 C. for 30 minutes and then filtered. The filtrate so obtained is next poured into 3 l. of ice Water with st rring and the solid which forms collected by filtration, washed with ether, dried and recrystallized twice from benzene-hexane to yield N-carboethoxy-4- chlorophthallimide.

(D) To 30 ml. of water at room temperature are added 5.44 g. (0.02 mole) of 7-aminocephalosporanic acid, 5.75 g. of sodium carbonate and 5.06 g. (0.02 mole) of N-carboethoxy 4 chlorophthallimide. The mixture is stirred for 20 minutes and then filtered. Acidification of the filtrate forms a solid material which is collected by filtration, ried, and recrystallized from dimethylformamide to yield 7-(4-chlorophthallimido)-cephalosporanic acid.

Example 4 To 15 ml. of water at room temperature are added 2.72 g. (0.01 mole) of 7-aminocephalosporanic acid, 2.63 g. of sodium carbonateand 2.18 g. (0.01 mole) of N-carboethoxyphthallimide. The mixture is stirred for 20 minutes and filtered. Upon acidification of the filtrate, the solid which forms is collected by filtration, immediately washed with water, dried and recrystallized from dimethylformamide to yield 7-phthallimidocephalosporanic acid.

Example 5 3-ethylphthallic acid (174 g.) is employed in the procedure of Example 3 in place of 4-chlorophthallic acid. Upon completion of the steps therein described in parts A, B and C of that example then yields the compound N-carboethoxy-3-ethylphthallimide.

In a similar fashion by employing equivalent amounts of 4-methylphthallic acid, 3-t-butylphthallic acid, and 3-isopropyl-S-methylphthallic acid. There are respectively obtained the compounds N-carboethoxy-4-methylphthallimide, N-carboethoxy 3 butylphthallimide, and N-carboethoxy-3-isopropyl-S-methylphthallimide.

In a similar fashion the following compounds are subjected in equivalent amounts to the aforementioned procedures of Example 3: 3-bromophthallic acid, 4-iodophthallic acid, 4-ethoxyphthallic acid, 3-methoxyphthallic acid, 3-nitrophthallic acid, and 3-chloro-6-methoxyphthallic acid.

Example 6 By substituting 7-aminocephalosporanic acid for 6-aminopenicillanic acid in the procedure of Example 3, part D and employing the N-carboethoxy substituting phthallimides prepared in Example 5, there are obtained the compounds 7 (4-methylphthallimido) cephalosporanic acid, 7-(3-butylphthallirnido)-cephalosporanic acid, 7-(3- isobutyl '5 methylphthallimido) cephalosporanic acid, 7-(3-bromophthallimido)-cephalosporanic acid, 7-(4-iodophthallimido)-cephalosporanic acid, 7-(4-ethoxyphthallimido)-cephalosporanic acid, 7-(3-methoxyphthallimido)-cephalosporanic acid, 7-(3-nitrophthallimido)-cephalosporanic acid, and 7-(3-chloro 6 methoxyphthallimido) -cephalsoporanic acid.

Example 7 There is substitutedfor 3-chlorophthallic acid in the procedure of Example 3, g. of cyclohexene-4,5-dicarboxylic acid. Upon completion of the steps therein described, there is obtained the compound 7-(cyclohexene-4,5-dicarboxyirnido)-cephalosporanic acid.

Similarly by employing equivalent amounts of 3-methylcyclchexene-4,5-dicanboxylic acid, there is obtained the compound 7-(3-methylcyclohexene-4,5-dicarboxyimid0) cephalosporanic acid.

Likewise there are employed the compounds hexane- 1,2-dicarboxylic acid, hexane-2,3-dicarboxylic acid, 1,4- cyclohexadiene-l,2-dicarboxylic acid, and 1,3-cyclohexadiene-2,3-dicarboxyiic acid and thus obtained are the compounds 7 (hexane-ll dicarboxyimido)-cephalosporanic acid, 7- (hexane-2,3-dicarboxyimido)-cephalosporanic acid, 7-(1,4-cyclohexadiene-1,2dicarboxyimido)- cephalosporanic acid and 7-(1,3-cyclohexadiene-2,3-d icarboxyimido) -cephalosporanic acid.

Example 8 Two hundred and thirteen grams of 3,4-dichlorocyclobutane-1,2-dicarboxyl-ic acid are employed in the procedure of Example 3 and there is thus obtained upon execution of the recited steps the compound 7-(3,4-dichlorocyclobutane 1,2-dicarboxyimido)-cephalosporanic acid.

Example 9 Forty-nine grams of succinimide is subjected to the reaction procedure described in Example 3, part C and there is thus obtained the compound N-carboethoxy succinimide. Use of this compound in part D of Example 3 in substitution for N-carboethoxy-4-chlorophthallimide, then yields the compound 7-succinimidocephalosporanic acid.

Use of meth-ylsuccinic acid in the procedure of Example 3, parts A, B and C yields N-canboethoxymethylsuccinimide which is employed in an analogous fashion to yield 7-methylsuccinimidocephalosporanic acid respectively.

Likewise ufl-dibromosuccinic acid is employed according to these procedures to obtain 7-(a,fi-dibromosuccinimido)-cephalosporanic acid.

Example 10 Maleimide (48 g.) is treated with ethylchloroformate in triethylarnine and dimethylformamide according to the procedure of Example 3, part C. There is thus obtained N-carboethoxymaleirnide which when employed to treat 7-aminocephalosporanic acid according to the meth- 0d of Example 3, part D yields 7-maleimidocephalosporanic acid.

Similarly citraconirnide, prepared fromcitriconic acid according to the procedure of Example 3, parts A and B is converted to the N-carboethoxy derivative in an analogous fashion and this compound employed in the treatment of 'I-aminocephalosporanic acid to yield 7-(citraconimido)-cephalosporanic acid.

Phenyl'sucoinic acid (174 g.) is employed in the procedure of Example 3 to yield sequentially the compounds phenylsuccinic acid anhydride, phenylsuccinimide, N- carboethoxyphenylsuccinimide and 7-phenylsuccinimidodecephalosporanic acid.

Likewise by the use of benzyls-uccin-ic acid, thereis obtained according to this procedure the compound 7-benzylsuccinimidocephalosporanic acid. In a similar fashion by the use of isopropylsuccinic acid and a-meth-yl-a-ethylsuccinic acid the execution of the steps of Example 3, there are obtained the compound 7-isopropylsuccinimidocephalosporanic acid and 7-(a-methyl-a-ethylsuccinimido)- cephalosporanic acid.

Example 11 Employing piperidine-3,4-dicarboxylic acid (160 g.) in the procedure of Example 3, parts A, B and C yields the compound pipen'dine-N-carboethoxy-3,4-dicarboxyimide. This reagent is employed to treat 7-aminocephalosporanic acid according to the procedure of Examplcfl, part I) to yield 7-(pipcridine-3,4-dicarboxyimido) -cephalosporanic acid.

In a 'similar fashion starting with 2,3-diphenylpiperazine-2,3-carboxyl-ic acid, there is obtained the compound 8 7 (2,3-diphenylpiperazine-2,3-dicarboxyimido)-cephalosporanic acid according to the above procedures.

Similarly from 2-oxopyrr0lidine-4,5-dicarboxylic acid and pyrrole-2,3-dicarboxylic acid, there are obtained according to the procedure of Example 3 the compound 7- (2-oxopyrrolidine-4,5 dicarb oxyimido) 4cephalosp oranic acid and 7-(pyrrole-2,3-dicarboxyimido)-cephalosporanic acid.

Use of pyridine-3,4-dicarboxylic acid in the procedure of Example 3 yields in a. similar fashion after conversion to the imide and thence to the N-carboethoxy derivative thereof, the compound 7-(pyridine-3,4-dicarboxyimido)- cephalosporanic acid.

Example 12 To 30 ml. of water at room temperature are added 4.56 g. (0.02 mole) of 3-hydroxymethyl-7-aminodecephalosporanic acid lactone, 5.75 g. of sodium carbonate and 3.5 g. (0.02 mole)'of N-carboethoxysuccinirnide (prepared as in Example 9). The mixture is stirred for 20 minutes and then filtered. Acidification of the filtrate forms a solid which is collected by filtration, dried and recrystallized from dimethylformamide to yield 3-hydroxymethyl-7-succlinimid odecephalosporanic acid lactone.

In a similar fashion the (following N-carboethoxyimides in equivalent amounts are substituted for N-carboethoxysuccinimide: N-carboethoxy 4 chlorophthallimide, N- carboethoxyphthallimide, N-carboethoxycyclohexene-4,5- dicauboxyimide, N-carboethoxymaleimide, N-carboethoxyphenyisuccimide, and N carboethoxy-2,6-piperidine- 3,4-dicarboxyimide. There are thus obtained respectively upon completion of the steps therein described in this example the compounds: 3-hydroxymethyl-7-( l-chlorophthallimido)-decephalosporanic acid lactone, 3-hydr0-xymethyl-7-(phthallimido)-decephalosporanic acid lactone, 3-hydroxymethyl 7 (cyclohexene-4,5-dicarboxyimido)- decephalosporanic acid lactone, 3-hyd'roxymethyl-7-(maleimido)-decephalosporanic acid lactone, 3hydroxymethyl- 7- (phenylsuccinimi-do)-decephalosporanic acid lactone, and 3 hydroxymethyl-7-(2,6-piperidine-3,4-dicarboxyimido)-decephalosporanic acid lactone.

Example 13 A preparation of acetylesterase obtained from the peels of 72 oranges according to the procedure of Jansen et al., Arch. Biochem., 15, 415 (1947) is added to l g. of 6- phthallimidocephalosporanic acid dissolved in 15 ml. of water. The pH is adjusted to 6 and maintained at or above thislevel for 15 hours. At the end of this time, the solution is passed through an IR 43 column (in the acetate form) and eluted with aqueous 0.1 M acetic acid which has been adjusted to pH 5.5 by the addition of sufiicient pyridine. The solution collected upon development of the column are adjusted to pH 8 by the addition of dilute sodium hydroxide, and this alkaline mixture then evaporated in vacuo to yield 3-hydroxymethyl-7-phthallimidodecephalosporanic acid as a sodium salt.

To 1 g. of B-hydroxymethyl-7-phthalli-midodecephalosporanic acid in 10 ml. of collidine is added 5 ml. of propionyl chloride. The mixture is allowed to stand for 10 hours and at the end of this tirne poured into 25 ml. of ice water. The solid which is thus formed is collected by filtration, recrystallized from dimethylformamide and dried to yield 3-propionyloxymethyl-7-phthallimidodecephalosporanic acid.

In a similar fashion other lower alkanoyl chlorides such as butanoyl chloride or pentanoyl chloride may be employed in the place of propionyl chloride obtaining the corresponding compounds 3-butanoyloxymethyl-7-phthallimidodecephalosporanic acid and 3-pentanoyloxymcthyl- 7-phthallimidodecephalosporanic acid. In an analogous fashion benzoyl chloride is employed in the place of these lower alkanoyl chlorides and there is thus obtained 3-ben- Zoyloxymethyl-7-phthallimidodecephalosporanic acid.

By substituting 7-succinimidocephalosporanic acid, 7-

malcimidocephalosporanic acid, and 7-phenylsuccinimidocephalosporanic acid for 7-phthallimidocephalosporanic acid in the procedure of the present example and then esterifying as also herein described, there are obtained the compound 3-propionyloxymethyl 7 succinimidodeceph alosporanic acid, 3-propionyloxymethyl-7-maleimidodecephalosporanic acid, 3-propionyloxymethyl-7-phenylsuccinimidodecephalosphoranic acid.

By employing benzoyl chloride in place of propionyl chloride in the esterification step following the enzymatic hydrolysis, the following compounds are obtained: 3- benzoyloxymethyl-7-succinimidodecephalosporanic acid, 3-benzoyloxymethyl-7-maleimidodecephalosporanic acid, and 3-benzoyloxymethyl-7-phenylsuccinimidodecephalosporanic acid.

Example 14 One gram of 2-(4-chlorophthallimido)-cephalosporanic acid is dissolved in excess amyl acetate and titrated with dilute sodium hydroxide to pH 8. The solution is then reduced in volume and the crystals which formed are collected by filtration to yield the sodium salt of 7-(4-chlorophthallimido)-cephalosporanic acid.

Example 15 One gram of 7-(succinimido)-cephalosporanic acid dissolved in excess amyl acetate and to the solution is added 10 g. of N-ethylpiperidine. The solution is stirred for 30 minutes and the crystals formed upon standing are collected by filtration and dried to yield the N-ethylpiperidinium salt of 7-succinimidocephalosporanic acid.

In a similar fashion by employing triethylamine, there is obtained 7-succinimidocephalosporanic as the triethylamine salt.

We claim: 1. Compound of the structural formula:

I COOM wherein A is a member of the group consisting of lower alkano- M is selected from the group consisting of hydrogen,

pharmaceutically acceptable nontoxic cations, an anionic charge when A is pyridinium, and when taken together with the group A a monovalent carbonoxygen bond;

is a vicinially bound structure selected from the group consisting of lower alkylene of from 2 to 6 carbon atoms, lower alkenylene of from 2 to 6 carbon atoms, lower cycloalkylene of from 4 to 6 carbon atoms, lower cycloalkenylene of from 4 to 6 carbon atoms, phenyl lower alkylene, phenyl lower alkenylene of from 8 to 12 carbon atoms, phenylene, monolower alkylphenylene, monohalogenophenylene, monoloweralkoxyphenylene, pyridinylene, piperizinylene, piperidinylene and pyrrolylene.

2. 7-succinirnidocepl1alosporanic acid.

3. 7-maleimidocephalosporanic acid.

4. 7-phenylsuccinimidocephalosporanic acid. 5. 7-phthallirnidocephalosporanic acid.

No references cited. 

1. COMPOUND OF THE STRUCTURAL FORMULA: 